Decreased Pain Threshold and Enhanced Synaptic Transmission in the Anterior Cingulate Cortex of Experimental Hypothyroidism Mice

Abstract

BackgroundThyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice.ResultsHT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated γ-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins.ConclusionsThese results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.

Investigation of brain GABA+ in primary hypothyroidism using edited proton MR spectroscopy

“…The discrepancies may be due to methodological differences in establishment of animal models, duration of hypothyroidism or the brain regions between studies. Moreover, decreased GABAergic neurotransmission, as demonstrated by the decrease in the recorded mIPSCs, was detected in the ACC of hypothyroid mice . The present study showed decreased GABA+ in the ACC region, which is consistent with decreased synaptic currents, although MRS does not report directly on GABA receptor activity.…”

Role of thyroid dysimmunity and thyroid hormones in endometriosis

“…The presence of high levels of thyroid antigens like TG, thyroid hormones, or TSHR in endometriotic cells may favor their exposure to the immune system in an immunostimulant environment that could trigger the breach of tolerance and the autoimmune reaction toward the thyroid autoantigens. On the other hand, the local synthesis of thyroid hormones can activate neutrophils and macrophages to locally promote a proinflammatory environment (38,39) and ROS production that may favor endometriotic cell proliferation (40). For these reasons, our endometriosis model is an autologous graft model of the uterine horn, which kept the mice immunocompetent (41).…”

“…For these reasons, our endometriosis model is an autologous graft model of the uterine horn, which kept the mice immunocompetent (41). Our endometriosis model was further coupled with a hypothyroid model (40), an autoimmune thyroiditis with hyperthyroidism (42), and an autoimmune thyroid condition with euthyroidism (24). Our model of hyperthyroidism is an experimental model of autoimmune thyroiditis, mimicking Hashimoto's disease, known to generate a hypothyroid condition (42).…”

“…2016040716219897). Three murine models have been developed: toxic hypothyroiditis induced in mice by MMI and potassium perchlorate (40), EAT induced by immunization with pTg (42), and thyroid immunization with euthyroidism induced by immunization with hTg (24). Each thyroid disorder model was coupled with an endometriosis model induced in immunocompetent mice by a syngeneic graft of uterine horns to generate endometriosis-like lesions as described (41) (SI Appendix, S13 and S14).…”

Characterization of risk factors for adjuvant radiotherapy-associated pain in a tri-racial/ethnic breast cancer population

“…Among the 11 comorbid conditions, diabetes, hypertension, or thyroid disease may increase pain intensity through modulating pain hypersensitivity/threshold, systemic inflammation, and/or radio-sensitivity [44]. Our previous study demonstrated that comorbid conditions increased inflammatory biomarker in radio-sensitivity and skin toxicity, particularly among obese breast cancer patients [35].…”